Researchers try to understand naked mole rats' resistance to cancer

With their pinkish, translucent and wrinkly skin, double-saber buck teeth and black-bead eyes, naked mole rats look like characters in a nightmare from hell. In fact, they do live underground in pitch-dark burrows where their air, from a human point of view, can contain chokingly little oxygen, toxic carbon dioxide levels and a perpetual stench of ammonia. What's more, even though they are mammals, these sausage-size rodents live more like ants and bees, with a queen, a few mating males and lots of workers.

In the past few years, researchers have been teasing out the biological bases for this cancer resistance, which they say may help explain how naked mole rats manage to live almost 10 times longer than their house mouse and street rat cousins. When Old Man, the oldest known naked mole rat on the planet, died at the University of Texas Health Science Center in San Antonio in November, he was 32 years old.

"These animals beat the odds and defy the aging process," says Rochelle Buffenstein, a physiologist at the center who had her scientific eye on Old Man since 1980, when she and colleagues captured him in a Kenyan sweet potato field. Now she maintains colonies with about 2,000 naked mole rats in her lab.

"A key finding of our work is that every physiological and biochemical system within the naked mole rat shows extended maintenance, leading to good health." Only in Old Man's final few years did he begin to appear sort of old. For most of his senior citizenhood, Buffenstein and her colleagues observed, his bones, muscles, heart and libido seemed like those of a teenager.

Getting old without the usual diseases and diminishments of the aging process has always been an intriguing idea. Vera Gorbunova, a biologist and cancer researcher at the University of Rochester in New York, is among those scientists trying to find out how naked mole rats do it. Most tantalizing to Gorbunova is that naked mole rats never get cancer even though 70 percent or more of mice that live even a few years die of cancer.

For many of the experiments her team wanted to do, they needed to grow naked mole rat cells in laboratory dishes, but this proved to be difficult. Whenever the cells touched one another, they stopped replicating. This was frustrating, but it also presented Gorbunova with a clue. She knew that normal mouse and human cells exhibit a less pronounced type of "contact inhibition" and that cancer cells grow into masses because they lack this inhibition.

"In naked mole rat cells," Gorbunova surmised, "we are seeing super contact inhibition." She wondered if there might be a linkage with the mole rats' immunity to cancer.

When the researchers dug deeper, they made a remarkable discovery that went all of the way down to the animals' genes and the biochemistry of their cells. "Naked mole rat cells possess two levels of contact inhibition, in contrast to the single level found in humans and mice," she and her colleagues wrote in late 2009 in the journal Proceedings of the National Academy of Sciences.

As Gorbunova sees it, living a long time and disease-thwarting mechanisms such as super contact inhibition go hand in hand. Mice are valuable animal models for studying cancer precisely because they get the disease so easily, she notes, and naked mole rats should become just as important for cancer research precisely because they never get the disease.

Her team is looking into potential therapeutic openings by which they might instigate super contact inhibition in other settings - say, in precancerous tissue of humans to stop the disease process in its tracks.

There's more to naked mole rats, though, than longevity and cancer resistance.

"Their pain biology is unique among animals," notes neuroscientist Thomas J. Park of the University of Illinois at Chicago. He and his colleauges have observed that the skin cells of naked mole rats lack certain pain-related signaling molecules. The animals appear undisturbed by acid and a hot-pepper irritant that bother other animals, including people. From this, the scientists hope to develop new means of pain management for humans.

Then there's the animals' ability to live without much oxygen. On that front, molecular evolutionary biologist Aaron Avivi of the University of Haifa in Israel and his colleagues have focused on the Spalax genus of mole rat, which he describes as a "hairy sausage whose ends are hard to tell apart."

Unlike the naked mole rat, Spalax individuals live solitary lives, are aggressive and cannot be bred in captivity. "Living underground has led to a lot of adaptations," Avivi says, including the ability to thrive in atmospheres that would quickly kill a human.

Especially during the winter in their northern Israeli habitats, there are days of intense rain that flood the mole rats' sealed tunnel systems. Oxygen concentrations dive to one-seventh that of normal above-ground levels, while carbon dioxide levels spike by a factor of 200, conditions that would permanently off most other air-breathing animals. Avivi says that developing a full understanding how the animals can shrug off such conditions holds great biomedical promise because of "its connection to ailments that practically kill the Western world," among them cancer, vascular and heart disease, heart attacks and strokes.

If for the past 24 million years you and your ancestors have lived in dark, dank subterranean niches, as have naked mole rats, you will have evolved plenty of adaptations in response to your habitat. And understanding those adaptations might well help us above-ground naked.